There is an increasing need for improved treatments for stroke patients as stroke is a common, devastating and extremely costly disease to the health care system. Forty percent of acute ischemic stroke patients are hyperglycemic upon arrival to the hospital. Hyperglycemia is associated with worse clinical outcome but it is unclear if tight glucose control can improve outcome. Severe or prolonged hypoglycemia can also be very damaging to ischemic brain. Clinical equipoise exists and current American Heart Association Guidelines encourage clinical trials to provide evidence on how to treat hyperglycemic acute stroke patients. The SHINE Trial is a multicenter, randomized, single blind (double blind outcomes) Phase III trial of 1400 patients at 56 sites across the United States. Patients will be randomized to IV insulin with tight glucose control (80-130 mg/dL) versus standard sliding scale subcutaneous insulin (<180 mg/dL). The primary outcome will be a severity adjusted dichotomized modified Rankin score (mRS) (responder analysis). The specific aims for this trial are: 'Specific Aim 1: To determine the efficacy of tight glucose control to a target range of 80-130 mg/dL with IV insulin infusion in hyperglycemic acute ischemic stroke patients within 12 hours of symptom onset (and 3 hours of arrival to ED) as measured by mRS at 90 days after stroke. Hypothesis 1: Tight glucose control (target 80-130 mg/dL) with IV insulin infusion therapy using eProtocol-insulin, a validated computerized decision support tool, will increase the severity adjusted 90 day favorable outcome on the mRS by an absolute 7% or more, as compared to the control group. Specific Aim 2: To determine the safety of tight glucose control with IV insulin infusion in hyperglycemic acute ischemic stroke patients treated for up to 72 hrs. Hypothesis 2: Tight glucose control with IV insulin infusion therapy using eProtocol-insulin is safe as determined by a severe hypoglycemia rate (<40 mg/dL) of less than 4%. PUBLIC HEALTH RELEVANCE: Stroke is the most common cause of adult disability and the third most common cause of death in the U.S. Forty percent of acute ischemic stroke patients are hyperglycemic and hyperglycemia is associated with worse clinical outcome but clinicians do not have data on how to manage the hyperglycemia. The SHINE trial is a Phase III efficacy and safety trial of glycemic control and the results will guide clinical practice all over the nation and the world.